Gene by environment interactions (non-additive combination of genetic and environmental influences) are deemed important in the etiology of alcoholism but are difficult to investigate in human beings. Various kinds of ethanol exposure (EE) during the 6th through 12th week of life (Periadolescence) increases alcohol preference (AP) in male and female BALB/cByJ but their effects on AP in BALB/cJ mice are absent or dissipate with time, the unequal effects of EE in the 2 strains providing a potential model for the study of gene by environment interactions in this important mammalian system. A series of experiments are proposed to refine experimental protocols and examine the effects of EE in males and females in enough detail to facilitate future molecular studies. First, a factorial design will combine variations in the Age of Exposure to EE (periadolescence vs. early adult) with differences in the interval (Immediate, 7 and 14 weeks) between EE cessation and AP testing. This will carefully compare the effects of EE at different ages and examine the durability of EE effects on AP. Secondly, the effectiveness of a short duration of EE (12 days) to increase AP will be tested. The main goal of this experiment is to improve the efficiency and economy of the experimental model. Ethanol metabolism will be compared in all animals from Experiments 1 and 2 to examine the role that differences in ethanol metabolism may play in the strain differences in the effects of EE on AP. Finally, a comparison will be conducted of the effects of EE on 3 mouse strains (129/P3J, C3H/HeJ, CE/J) carefully matched for low alcohol preference to discover if variation in response to EE is found among other strains. The results of this study may help identify progenitor strains that may be useful for mapping of the genes underlying variability in response to EE. The growing human literature on the harmful effects of alcohol abuse on brain morphology and function among adolescents emphasizes the importance of developing a preclinical model incorporating important individual differences in response to EE. Overall, these studies will establish a mouse model for the study of genetic factors and sex as they influence individual differences in response to ethanol exposure during adolescence and early adult life.